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. 2024 May 23:6:100185.
doi: 10.1016/j.crphar.2024.100185. eCollection 2024.

Liraglutide improves adipose tissue remodeling and mitochondrial dynamics in a visceral obesity model induced by a high-fat diet

Vanessa Touceda  1   2 , Florencia Fontana Estevez  1 , Leonardo Cacciagiú  2   3 , Paola Finocchietto  4 , Romina Bustos  1 , Agustina Vidal  1 , Gabriela Berg  5 , Celina Morales  6 , Germán González  1 , Veronica Miksztowicz  1   2
Affiliations

Liraglutide improves adipose tissue remodeling and mitochondrial dynamics in a visceral obesity model induced by a high-fat diet

Vanessa Touceda et al. Curr Res Pharmacol Drug Discov. .

Abstract

Central obesity is characterized by visceral adipose tissue (VAT) expansion, considered one of the main risk factors for metabolic complications. In recent years, new drugs have been studied for obesity treatment. Liraglutide (LGT), a GLP-1 agonist, decreases body weight, however, several mechanisms of action on VAT are still unknown.

Aim: to study the effect of LGT on factors associated with VAT remodeling and mitochondrial dynamics in mice fed a high-fat diet (HFD).

Methods: C57BL/6 mice were divided into Control (C) and HFD. After 15 weeks of feeding, each group was subdivided according to LGT administration for 5 weeks: C, C + LGT, HFD, and HFD + LGT. In epididymal AT (EAT) we evaluated histological and mitochondrial characteristics, vascularity, gelatinase activity (MMPs), and galectin-3 expression.

Results: HFD presented larger adipocytes (p < 0.05), and lower vascular density and MMP-9 activity (p < 0.01) than C, while a major number of smaller adipocytes (p < 0.05) and an increase in vascularity (p < 0.001) and MMP-9 activity (p < 0.01) was observed in HFD + LGT. Collagen content was higher (p < 0.05) in EAT from HFD and decreased in HFD + LGT. In C, C + LGT, and HFD + LGT, mitochondria were predominantly tubular-shaped while in HFD mitochondria were mostly spherical (p < 0.001).

Conclusion: LGT positively influences VAT behavior by modulating gelatinase activity, enhancing vascularization, and improving adipocyte histological characteristics. Additionally, LGT improves mitochondrial dynamics, a process that would favor VAT functionality.

Keywords: Liraglutide; Metalloproteinase; Vascular density; Visceral adipose tissue.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Analysis of histological characteristics of visceral adipose tissue by hematoxilin-eosin staining. Representative images of H-E-stained sections (A) and histological characteristics of epididymal adipose tissue: adipocyte area (B), adipocyte density (C) and vascular density (D) in Control (C), Control + LGT (C + LGT), HFD and HFD + LGT group. Ad: Adipocytes. Arrows: Blood vessels. Data are presented as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001.
Fig. 2
Fig. 2
Evaluation of vascular density in visceral adipose tissue by fluorescence assay. Representative images of rhodamine labeled GSL lectin, fluorescein peanut agglutinin lectin and DAPI stained sections of representative epididymal adipose tissue samples (n = 2 per group, 5 field per sample). Control (A), Control + LGT (B), HFD (C) and HFD + LGT (D) groups. Data are presented as mean ± SD. *p < 0.05.
Fig. 3
Fig. 3
Gelatinolytic activity evaluation in visceral adipose tissue by zymography. MMP-2 and -9 activity in epididymal adipose tissue from Control (C), Control + LGT (C + LGT), HFD and HFD + LGT group. RU, relative units. Data are presented as mean ± SD. **p < 0.01.
Fig. 4
Fig. 4
Measurement of interstitial collagen content in visceral adipose tissue by Picrosirius Red staining. Representative images of Picrosirius Red stained sections and collagen volume fraction (%) quantification in epididymal adipose tissue from Control (C), Control + LGT (C + LGT), HFD and HFD + LGT group. Arrows: Interstitial collagen. Data are presented as mean ± SD. *p < 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 5
Fig. 5
Quantification of Galectin-3 expression in visceral adipose tissue by western blotting. Galectin-3 levels in epididymal adipose tissue from Control (C), Control + LGT (C + LGT), HFD and HFD + LGT group. RU, relative units. Data are presented as mean ± SD. *p < 0.05.
Fig. 6
Fig. 6
Analysis of mitochondrial morphology in adipose tissue by transmission electron microscopy. Representative images of mitochondrial morphology by electron microscope images (30.000× magnification). Tubular and fragmented mitochondria were counted per arbitrary area and expressed in percentage. ***p < 0.001.
Fig. 7
Fig. 7
Quantification of Uncoupling protein-1 (UCP-1) expression in visceral adipose tissue by western blotting. UCP-1 levels in epididymal adipose tissue from Control (C), Control + LGT (C + LGT), HFD and HFD + LGT group. RU, relative units. Data are presented as mean ± SD.
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